1. Field of the Invention
The present invention is concerned with pharmaceutical injectable preparations comprising a potentiated sulfonamide for administration to mammals by the intramuscular route.
2. Brief Description of the Prior Art
The treatment of bacterial infections with sulfonamides has been known for several decades. Although their action on each microorganism differs due to cross resistance, a variety of these chemotherapeutic agents show similar potency. Their antibacterial activity is notably increased when sulfonamides are administered in combination with a potentiator agent of the 2,4-diaminopirimidine group (Brit. Med. J. 410 (8) 1978; Postgrad. Med. J., 45 (Suppl.) 56, 1969). According to this reference various combinations between sulfonamides and potentiators have been developed. The combinations vary either in the chemical structure of agents or in the proportion of sulfonamide and potentiator used in the preparation.
Several potentiated sulfonamides are described in the prior art (German Pat. Nos.: 2.445.440; 2.538.678; 2.627.706; 2.631.780; 2.638.052; and 2.818.281; Belgium Pat. No.: 851.060; Swiss Pat. No.: 544.053; Argentine Pat. Nos.: 172.760; 188.083; and 204.521). The prior art sulfonamide compounds have the following basic chemical structure: ##STR1## where R is substituted heterocycle, such as: pyridazine, pyrimidine, isoxazol and quinoxaline. For example, in the 4-amino-N-pyridazinylbenzene sulfonamide class there are: sulfamethoxy pyridazine and sulfaethoxy pyridazine. In the class of 4-amino-N (2- or 4-pyrimidinyl) benzene sulfonamides there are: sulfadoxine, sulfadiazine, sulfadimetoxine, sulfadimidine, sulfisomidine, sulfametoxidiazine and the like. Sulfametoxazol and sulfioxazol are representative 4-amino-N-(3'- or 5'-isoxazolyl) benzenesulfonamides. Another sulfonamide is sulfaquinoxaline (chemically named 4-amino-N (2-quinoxalinyl) benzenesulfonamide). Sulfamoxol is representative of a 4-amino-N (2-oxazolyl) benzenesulfonamide.
Potentiators used in combination with sulfonamides may be substituted 2,4-diaminopyrimidines of formula: ##STR2## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each selected from hydrogen and methoxy groups. Representatives of the potentiators of Formula II are trimethoprim (5-3', 4', 5'-trimethoxy-benzyl)-2,4-diaminopyrimidine, ormethoprim (5-(3', 4'-dimethoxy -6'-methylbenzyl)-2,4-diaminopyrimidine) and diaveridine (5-3',4'-dimethoxybenzyl)-2,4-diaminopyrimidine).
The proportions of sulfonamide and potentiator used and described in the literature, is generally in a range of 1:1 to 20:1, preferably 5:1 (that is, 5 parts in weight of sulfonamide and 1 part in weight of potentiator).
Although the combination of sulfonamide and potentiator is more frequently used by oral route, several injectable preparations (which are able to give an antibacterial action faster than that obtained with tablets, capsules or suspensions) were previously known. During the development of the known injectable pharmaceutical preparations containing sulfonamides and their potentiator, several problems arose. According to the patent literature only a few of these problems were solved. For example, it is a very well known fact that sulfonamides are solubilized in water by the addition of pharmaceutically acceptable inorganic bases, such as sodium hydroxide, ammonium hydroxide or organic bases, such as triethanolamine, diethanolamine, monoethanolamine, meglumine and the like. However, potentiators such as those of the 2,4-diaminopyrimidine class (which have basic characteristics) are soluble in water only when they are salifyied with certain acids. The mixture of both solutions, gives a precipitate formed of the separate components. Precipitation of course impeded injectability of the preparation.
Another problem in the preparation of this kind of injectable formulation concerns its pH. When sulfonamides and potentiators are put into water at a pH near to 7, they may react giving an insoluble complex formed by one mole of sulfonamide and one mole of potentiator (see Japanese Patent No.: 73013511). To solve this problem, some investigators have followed two different courses. In the first course the components are first dissolved in water-miscible organic solvents, such as dimethylacetamide, ethanol, propyleneglycol, low molecular weight polyethyleneglycols and the like. In the second course, the sulfonamide is dissolved in water by the addition of bases, such as sodium hydroxide or diethanolamine and the potentiator, in microcrystalline form, is suspended in the solution. In the first case, that is, when water-miscible organic solvents are used, the resulting injectable preparations exhibit poor stability and provoke a high degree of irritation at the injection site. In some cases, irreversible tissue necrosis may occur. Several examples of these unstable, irritating preparations are known. For example, an injectable composition containing sodium sulfonamide and trimethoprim dissolved in a medium formed by polyethyleneglycol 400, ethanol, dimethylacetamide, diethanolamine and water is described in French Pat. No.: 1.523.606. Also, sulfonamide and trimethoprim have been dissolved in a mixture of water and dimethylacetamide (German Pat. No.: 2.445.400). In another injectable preparation (described in German Pat. No.: 2.538.678) sulfonamide and 2,4-diaminepyrimidine type potentiator are dissolved in a mixture of polyethyleneglycol, ethanol, citric acid, sodium hydroxyde and water. Other injectable solutions containing sulfonamide, trimethoprim, ethanol, propyleneglycol, polyvinylpyrrolidone and water are described in German Pat. Nos.: 2.631.779 and 2.631.780. Also representative of this state of the art is the disclosure found in U.S. Pat. No. 4,031,214.
Injectable suspensions of the prior art have the same stability problems associated with the solutions. They also pose other problems. For example, microcrystalline particles in suspension tend to form aggregates which precipitate in the bottom of vials and grow over a period of time. Consequently, the suspensions may not flow through needles commonly used for injections. The physical stability of these suspensions may be improved by adding certain vehicles which increase their viscosity. However, the increase of viscosity lowers syringeability. Another problem commonly observed in solutions as well as in suspensions, is the formation of small crystals of a sulfonamide-potentiator complex. The low diffusion of such a preparation at the injection site and the high pH (typically greater than 10), provoke local irritation and even irreversible necrosis (see Rasmussen, F.; Svensen, O.: Res. Vet. Sci., 20, 50 (1) 1976).
The present invention is of a potentiated sulfonamide preparation for injection, possessing greater stability than the prior art preparations, without the aforementioned problems. The preparations of the invention, upon intramuscular administration, do not provoke irritation or cause irreversible tissue alteration at the injection site. They exhibit excellent syringeability.